It is estimated that 169,500 patients were diagnosed with lung cancer in the United States in 2001, and 157,400 died as a result of the disease. Lung cancer causes more death than colorectal cancer, breast cancer and prostate cancer combined. (1) Five-year survival rates have improved from 8% in the early 1960's to 15% in the early 1990's. This doubling of the 5-year lung cancer survival rate is encouraging and has resulted in a shift from the previous nihilism associated with lung cancer treatment to a guarded optimism regarding outcome from treatment. Although locoregional control of non-small-cell lung cancer (NSCLC) can be achieved by surgery and radiation, more than 70% of relapses in patients with stage I disease occur at distant sites. (2) Thus, most patients with NSCLC must have systemic disease, even at the earliest stages. Efforts at improving the management and outcome of patients with this disease are evolving. Recent efforts have been directed at chemoprevention to reduce incidence and at neoadjuvant and adjuvant chemotherapy to reduce the high systemic relapse rate.
Cytotoxic intervention strategies have associated toxicities, particularly in this target population where rates of comorbidities from atherosclerotic disease and chronic benign lung disease are high. Directing treatment strategies toward patients with NSCLC most likely to benefit has been guided by clinical variables such as disease stage, performance status, and weight loss. Other pathologic and molecular variables include submicroscopic metastases, (3) metabolic activity by imaging, (4) expression of proteins in various pathways regulating cellular growth and differentiation, (5-7) mutations in oncogenes and tumor suppressor genes, (8-12) expression of extracellular matrix proteinases and markers of angiogenesis, (13-15) and genome instability.
The predominant type of genome instability in cancer is structural aberration of chromosomes, i.e., deletions, translocations, and insertions. These are thought to arise as a result of impaired repair of DNA double-strand breaks by homologous recombination and non-homologous end joining. (16,17) Loss of heterozygosity (LOH) analysis is the most frequently used technique to assess genome instability, and allele loss often heralds the discovery of genes with key functions in tumor development and progression. (18)
Prior to the present invention, few investigations have shown significant associations between LOH and survival of patients with lung cancer. LOH (4/40) at chromosome segment 11p13 was predictive of poor outcome in squamous cell carcinomas with a p-value of 0.02, (20) and LOH (21/66) for the HRAS locus near the telomere of 11p was predictive of poor outcome for all histopathologic subtypes with a p-value of 0.04. (25) However, Sanches-Cespedes et al. did not find such an association despite comparable numbers of cases studied and similar frequencies of LOH (12/63 for 11p13 and 19/61 for the HRAS locus). (26) Three regions of LOH on chromosome 3p, namely 3p14, 3p21, 3p25-26, have been investigated for associations with survival. In one study of 110 patients with NSCLC, LOH was found in 45 of 98 informative cases, and there was a trend towards poor survival (p=0.0631). (27) A second study with 35 patients in pathologic stage I showed no trend towards poor survival, (24) as did a third study with 103 patients. (28) The APC/MCC tumor suppressor gene is located on segment 5q21. LOH was significantly correlated with poor survival (p=0.01, LOH in 22/75 NSCLCs) in one study (40) but not in a second study (p=0.33, 14/68 NSCLCs). (26) These results suggest that LOH per se, as a marker of chromosomal instability resulting from impaired repair of DNA double-strand breaks, does not appear to be prognostically useful. Thus, there is a need for identifying loci wherein the presence of LOH could be reliably used for prognosis.